Sickle cell disease (SCD) is one of the most frequent of inherited hemoglobinopathies. Although the genetics and pathophysiology of the disease are well characterized, it was recently described as a "simple disease with no cure". Three percent of all African-Americans have SCD. Fifteen percent of patients die by age 20 and 50 percent by age 40. Bone marrow transplantation (BMT) has been demonstrated to cure SCD. However, the morbidity and mortality associated with conventional BMT, especially graft versus host disease (GVHD) and lethal conditioning, have limited the widespread application of BMT to treat SCD. Only 20 percent of patients with SCD have an HLA-identical family member donor. For the remainder of patients who do not have a matched family member donor, a substantial risk for GVHD exists, since the incidence and severity of GVHD is directly correlated with the degree of genetic disparity between donor and recipient. It would be of significant impact if a nonlethal approach to achieve a mixed chimeric state in patients with SCD, with partial replacement of the defective RBC, could be achieved without substantial risk of GVHD. This study addresses the problems of (1) high toxicity; (2) fear of early mortality; and (3) lack of suitably matched donors, using a new approach to BMT. The goal is to reverse the risk/benefit ratio for BMT for patients with SCD. A novel donor bone-marrow-derived cell, separate from the hematopoietic stem cell (HSC), has been identified that facilitates engraftment of purified donor HSC in allogeneic recipients without producing GVHD. Because BMT has been demonstrated to cure SCD when an HLA-identical sibling donor is available, in AIM I we will APPLY THE FACILITATING CELL PROTOCOL TO CONVENTIONAL BMT FOR SICKLE CELL DISEASE. By processing the marrow to remove all undesired cells, we hope to enhance engraftment and avoid GVHD. In AIM II we will ESTABLISH A PARTIAL CONDITIONING APPROACH To MIXED CHIMERISM IN CHILDREN WITH SICKLE CELL DISEASE WHO DO NOT HAVE A SUITABLY MATCHED DONOR. We will MONITOR CHIMERISM AND IMMUNOLOGIC RECONSTITUTION in both cohorts of patients (AIM III). SCID is a chronic ailment with significant morbidity including painful crises, bacterial infections, missed school or work days, and frequent hospitalizations. In AIM IV, we will ASSESS QUALITY OF LIFE in patients who engraft as chimeras. Our overall objective is to apply BMT to treat SCD, yet avoid the morbidity and mortality of lethal conditioning, GVHD, and lack of suitably matched donors.